Mitochondrial DNA damage is a hallmark of chemically induced and the R6/2 transgenic model of Huntington's disease.
Many forms of neurodegeneration are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage, however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are primary events in the delayed onset observed in Huntington's disease (HD). We hypothesize that an age-dependent increase in mtDNA damage contributes to mitochondrial dysfunction in HD. Two HD mouse models were studied, the 3-nitropropionic acid (3-NPA) chemically induced model and the HD transgenic mice of the R6/2 strain containing 115-150 CAG repeats in the huntingtin gene. The mitochondrial toxin 3-NPA inhibits complex II of the electron transport system and causes neurodegeneration that resembles HD in the striatum of human and experimental animals. We measured nuclear and mtDNA damage by quantitative PCR (QPCR) in striatum of 5- and 24-month-old untreated and 3-NPA treated C57BL/6 mice. Aging caused an increase in damage in both nuclear and mitochondrial genomes. 3-NPA induced 4-6 more damage in mtDNA than nuclear DNA in 5-month-old mice, and this damage was repaired by 48h in the mtDNA. In 24-month-old mice 3NPA caused equal amounts of nuclear and mitochondrial damage and this damage persistent in both genomes for 48h. QPCR analysis showed a progressive increase in the levels of mtDNA damage in the striatum and cerebral cortex of 7-12-week-old R6/2 mice. Striatum exhibited eight-fold more damage to the mtDNA compared with a nuclear gene. These data suggest that mtDNA damage is an early biomarker for HD-associated neurodegeneration and supports the hypothesis that mtDNA lesions may contribute to the pathogenesis observed in HD.
Acevedo-Torres
Karina
K
University of Puerto Rico, Medical Sciences Campus, Department of Physiology and Biophysics, San Juan, PR, USA.
Berríos
Lexsy
L
Rosario
Nydia
N
Dufault
Vanessa
V
Skatchkov
Serguei
S
Eaton
Misty J
MJ
Torres-Ramos
Carlos A
CA
Ayala-Torres
Sylvette
S
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009574:Nitro Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology
D004272:DNA, Mitochondrial; D009574:Nitro Compounds; D011422:Propionates; D006151:Guanosine; C046215:8-hydroxyguanosine; C015392:3-nitropropionic acid